tbuckley/cabot-search huggingface dataset:
Ultrasensitive Detection of Circulating LINE-1 ORF1p as a Specific Multicancer Biomarker
Authors: Martin S. Taylor, Connie Wu, Peter C. Fridy, Stephanie J. Zhang, Yasmeen Senussi, Justina C. Wolters, Tatiana Cajuso, Wen-Chih Cheng, John D. Heaps, Bryant D. Miller, Kei Mori, Limor Cohen, Hua Jiang, Kelly R. Molloy, Brian T. Chait, Michael G. Goggins, Irun Bhan, Joseph W. Franses, Xiaoyu Yang, Mary-Ellen Taplin, Xinan Wang, David C. Christiani, Bruce E. Johnson, Matthew Meyerson, Ravindra Uppaluri, Ann Marie Egloff, Elyssa N. Denault, Laura M. Spring, Tian-Li Wang, Ie-Ming Shih, Jennifer E. Fairman, Euihye Jung, Kshitij S. Arora, Osman H. Yilmaz, Sonia Cohen, Tatyana Sharova, Gary Chi, Bryanna L. Norden, Yuhui Song, Linda T. Nieman, Leontios Pappas, Aparna R. Parikh, Matthew R. Strickland, Ryan B. Corcoran, Tomas Mustelin, George Eng, Ömer H. Yilmaz, Ursula A. Matulonis, Andrew T. Chan, Steven J. Skates, Bo R. Rueda, Ronny Drapkin, Samuel J. Klempner, Vikram Deshpande, David T. Ting, Michael P. Rout, John LaCava, David R. Walt, Kathleen H. Burns
Journal: Cancer Discovery (2023)

Abstract Improved biomarkers are needed for early cancer detection, risk stratification, treatment selection, and monitoring treatment response. Although proteins can be useful blood-based biomarkers, many have limited sensitivity or specificity for these applications. Long INterspersed Element-1 (LINE-1) open reading frame 1 protein (ORF1p) is a transposable element protein overexpressed in carcinomas and high-risk precursors during carcinogenesis with negligible expression in normal tissues, suggesting ORF1p could be a highly specific cancer biomarker. To explore ORF1p as a blood-based biomarker, we engineered ultrasensitive digital immunoassays that detect mid-attomolar (10−17 mol/L) ORF1p concentrations in plasma across multiple cancers with high specificity. Plasma ORF1p shows promise for early detection of ovarian cancer, improves diagnostic performance in a multianalyte panel, provides early therapeutic response monitoring in gastroesophageal cancers, and is prognostic for overall survival in gastroesophageal and colorectal cancers. Together, these observations nominate ORF1p as a multicancer biomarker with potential utility for disease detection and monitoring. Significance: The LINE-1 ORF1p transposon protein is pervasively expressed in many cancers and is a highly specific biomarker of multiple common, lethal carcinomas and their high-risk precursors in tissue and blood. Ultrasensitive ORF1p assays from as little as 25 μL plasma are novel, rapid, cost-effective tools in cancer detection and monitoring. See related commentary by Doucet and Cristofari, p. 2502. This article is featured in Selected Articles from This Issue, p. 2489
Rerouting the GPS Directing Immunotherapy in Endometrial Cancer
Authors: Rhea Jangra, Neesha C. Dhani
Journal: Clinical Cancer Research (2023)

Summary Mismatch repair (MMR) status alone is insufficient to guide the use of PD-(L)1 monotherapy in patients with endometrial cancer. Additional biomarkers, including tumor mutational burden and combined positive score, may help to identify patients with MMR-proficient tumors with a high probability of benefit from PD-(L)1 monotherapy, and those with MMR-deficient tumors who might require combination strategies. See related article by Oaknin et al., p. 4564
Proviral location affects cognate peptide–induced virus production and immune recognition of HIV-1–infected T cell clones
Authors: Filippo Dragoni, Abena K. Kwaa, Caroline C. Traut, Rebecca T. Veenhuis, Bezawit A. Woldemeskel, Angelica Camilo-Contreras, Hayley E. Raymond, Arbor G. Dykema, Eileen P. Scully, Amanda M. Rosecrans, Kellie N. Smith, Frederic D. Bushman, Francesco R. Simonetti, Joel N. Blankson
Journal: Journal of Clinical Investigation (2023)

BACKGROUNDHIV-1-infected CD4+ T cells contribute to latent reservoir persistence by proliferating while avoiding immune recognition. Integration features of intact proviruses in elite controllers (ECs) and people on long-term therapy suggest that proviruses in specific chromosomal locations can evade immune surveillance. However, direct evidence of this mechanism is missing.METHODSIn this case report, we characterized integration sites and full genome sequences of expanded T cell clones in an EC before and after chemoradiation. We identified the cognate peptide of infected clones to investigate cell proliferation and virus production induced by T cell activation, and susceptibility to autologous CD8+ T cells.RESULTSThe proviral landscape was dominated by 2 large clones with replication-competent proviruses integrated into zinc finger (ZNF) genes (ZNF470 and ZNF721) in locations previously associated with deeper latency. A third nearly intact provirus, with a stop codon in Pol, was integrated into an intergenic site. Upon stimulation with cognate Gag peptides, infected clones proliferated extensively and produced virus, but the provirus in ZNF721 was 200-fold less inducible. While autologous CD8+ T cells decreased the proliferation of cells carrying the intergenic provirus, they had no effect on cells with the provirus in the ZNF721 gene.CONCLUSIONSWe provide direct evidence that upon activation of infected clones by cognate antigen, the lower inducibility of intact proviruses in ZNF genes can result in immune evasion and persistence.FUNDINGOffice of the NIH Director and National Institute of Dental & Craniofacial Research; NIAID, NIH; Johns Hopkins University Center for AIDS Research.
Overview of epigenetic degraders based on PROTAC, molecular glue, and hydrophobic tagging technologies
Authors: Xiaopeng Peng, Zhihao Hu, Limei Zeng, Meizhu Zhang, Congcong Xu, Benyan Lu, Chengpeng Tao, Weiming Chen, Wen Hou, Kui Cheng, Huichang Bi, Wanyi Pan, Jianjun Chen
Journal: Acta Pharmaceutica Sinica B (2023)

Epigenetic pathways play a critical role in the initiation, progression, and metastasis of cancer. Over the past few decades, significant progress has been made in the development of targeted epigenetic modulators (e.g., inhibitors). However, epigenetic inhibitors have faced multiple challenges, including limited clinical efficacy, toxicities, lack of subtype selectivity, and drug resistance. As a result, the design of new epigenetic modulators (e.g., degraders) such as PROTACs, molecular glue, and hydrophobic tagging (HyT) degraders has garnered significant attention from both academia and pharmaceutical industry, and numerous epigenetic degraders have been discovered in the past decade. In this review, we aim to provide an in-depth illustration of new degrading strategies (2017–2023) targeting epigenetic proteins for cancer therapy, focusing on the rational design, pharmacodynamics, pharmacokinetics, clinical status, and crystal structure information of these degraders. Importantly, we also provide deep insights into the potential challenges and corresponding remedies of this approach to drug design and development. Overall, we hope this review will offer a better mechanistic understanding and serve as a useful guide for the development of emerging epigenetic-targeting degraders.
Tumor radiogenomics in gliomas with Bayesian layered variable selection
Authors: Shariq Mohammed, Sebastian Kurtek, Karthik Bharath, Arvind Rao, Veerabhadran Baladandayuthapani
Journal: Medical Image Analysis (2023)

We propose a statistical framework to analyze radiological magnetic resonance imaging (MRI) and genomic data to identify the underlying radiogenomic associations in lower grade gliomas (LGG). We devise a novel imaging phenotype by dividing the tumor region into concentric spherical layers that mimics the tumor evolution process. MRI data within each layer is represented by voxel-intensity-based probability density functions which capture the complete information about tumor heterogeneity. Under a Riemannian-geometric framework these densities are mapped to a vector of principal component scores which act as imaging phenotypes. Subsequently, we build Bayesian variable selection models for each layer with the imaging phenotypes as the response and the genomic markers as predictors. Our novel hierarchical prior formulation incorporates the interior-to-exterior structure of the layers, and the correlation between the genomic markers. We employ a computationally-efficient Expectation-Maximization-based strategy for estimation. Simulation studies demonstrate the superior performance of our approach compared to other approaches. With a focus on the cancer driver genes in LGG, we discuss some biologically relevant findings. Genes implicated with survival and oncogenesis are identified as being associated with the spherical layers, which could potentially serve as early-stage diagnostic markers for disease monitoring, prior to routine invasive approaches. We provide a R package that can be used to deploy our framework to identify radiogenomic associations.
Bidirectional Association Between Cardiovascular Disease and Lung Cancer in a Prospective Cohort Study
Authors: Shanshan Zhang, Lei Liu, Shanshan Shi, Heng He, Qian Shen, Haoxue Wang, Shifan Qin, Jiang Chang, Rong Zhong
Journal: Journal of Thoracic Oncology (2023)

The study aimed to prospectively investigate the bidirectional association between cardiovascular disease (CVD) and lung cancer, and whether this association differs across genetic risk levels.
Hematological effects of atypical and cameroon β‐globin gene haplotypes in adult sickle cell anemia
Authors: M. H. Steinberg, Z.‐H. Lu, R. L. Nagel, S. Venkataramani, P. F. Milner, L. Huey, S. Safaya, R. F. Rieder
Journal: American Journal of Hematology (1998)
Comprehensive Management of ANOCA, Part 1—Definition, Patient Population, and Diagnosis
Authors: Bruce A. Samuels, Samit M. Shah, R. Jay Widmer, Yuhei Kobayashi, Steven E.S. Miner, Viviany R. Taqueti, Allen Jeremias, Ahmed Albadri, John A. Blair, Kathleen E. Kearney, Janet Wei, Ki Park, Ailin Barseghian El-Farra, Noa Holoshitz, Katherine B. Janaszek, Manoj Kesarwani, Amir Lerman, Megha Prasad, Odayme Quesada, Harmony R. Reynolds, Michael P. Savage, Nathaniel R. Smilowitz, Nadia R. Sutton, Joseph M. Sweeny, Olga Toleva, Timothy D. Henry, Jeffery W. Moses, William F. Fearon, Jennifer A. Tremmel
Journal: Journal of the American College of Cardiology (2023)
Heart rate–corrected systolic ejection time: population-based reference values and differential prognostic utility in acute heart failure
Authors: Caroline Morbach, Isabelle Simon, Elisabeth Danner, Götz Gelbrich, Ulrich Stefenelli, Floran Sahiti, Nina Scholz, Vladimir Cejka, Judith Albert, Georg Ertl, Christiane E Angermann, Gülmisal Güder, Stefan Frantz, Peter U Heuschmann, Christoph Maack, Stefan Störk
Journal:  (2023)

Abstract Aims Systolic ejection time (SET) is discussed as a treatment target in patients with heart failure (HF) and a reduced left ventricular (LV) ejection fraction (EF). We derived reference values for SET correcting for its dependence on heart rate (SETc), and explored its prognostic utility in patients admitted with decompensated HF. Methods and results SETc was derived in 4836 participants of the population-based STAAB study (mean age 55 ± 12 years, 52% women). There, mean SETc was 328 ± 18 ms, increased with age (+4.7 ms per decade), was shorter in men than women (−14.9 ms), and correlated with arterial elastance (r = 0.30; all P &amp;lt; 0.001). In 134 patients hospitalized with acute HF, SETc at admission was shorter when compared with the general population and differed between patients with HF with reduced EF (HFrEF; LVEF ≤40%; 269 ± 35 ms), HF with mildly reduced EF (HFmrEF; LVEF 41–49%; 294 ± 27 ms), and HF with preserved EF (HFpEF; LVEF ≥50%; 317 ± 35 ms; P &amp;lt; 0.001). In proportional hazard regression, an in-hospital increase in SETc was associated with an age- and sex-adjusted hazard ratio of 0.38 (95% confidence interval 0.18–0.79) in patients with HFrEF, but a hazard ratio of 2.39 (95% confidence interval 1.24–4.64) in patients with HFpEF. Conclusion In the general population, SETc increased with age and an elevated afterload. SETc was mildly reduced in patients hospitalized with HFpEF, but markedly reduced in patients with HFrEF. In-hospital prolongation of SETc predicted a favourable outcome in HFrEF, but an adverse outcome in HFpEF. Our results support the concept of a U-shaped relationship between cardiac systolic function and risk, providing a rationale for a more individualized treatment approach in patients with HF.
High Targeting Specificity toward Pulmonary Inflammation Using Mesenchymal Stem Cell‐Hybrid Nanovehicle for an Efficient Inflammation Intervention (Adv. Healthcare Mater. 23/2023)
Authors: Yuanqin Su, Ting Huang, Hao Sun, Ruyi Lin, Xixi Zheng, Qiong Bian, Jinsong Zhang, Shihan Chen, Honghui Wu, Donghang Xu, Tianyuan Zhang, Jianqing Gao
Journal: Advanced Healthcare Materials (2023)

Mesenchymal Stem Cell-Hybrid Nanovehicles In article 2300376, Donghang Xu, Tianyuan Zhang, Jianqing Gao and co-workers develop a biomimetic nanovehicle hybridizing the cell membrane of mesenchymal stem cell with a liposome. This hybrid nanovehicle shows advantages of both highly efficient inflammation targeting and good drug-loading capacity, resulting in a specifically targeted delivery of methylprednisolone to inflammatory damaged lung cells. A single-dose administration of this hybrid nanovehicle achieves a prominent lung inflammation suppression, showing promising potential for the treatment against acute lung injury with reduced side effects.
Food‐induced immediate response of the esophagus in pediatric eosinophilic esophagitis
Authors: Gizem Koken, Hacer Ilbilge Ertoy Karagol, Sinem Polat Terece, Zeynep Cavdar, Kenan Cetin, Odul Egritas Gurkan, Sinan Sari, Buket Dalgic, Arzu Bakirtas
Journal: Allergy (2023)

Abstract Background Food‐induced immediate response of the esophagus (FIRE) is a new phenomenon that has been described in eosinophilic esophagitis (EoE) patients. It is suspected when unpleasant symptoms occur suddenly on contact of the triggering food with the esophageal surface and recur with repeated exposures. It can often be mistaken for pollen‐food allergy syndrome (PFAS) and solid food dysphagia. Data on FIRE is limited to one survey study and case reports, and there are no screening studies conducted on either adults or children with EoE. In this study, we aimed to screen children aged ≥7 years old with EoE for FIRE. Methods Demographic data were collected from medical records. A questionnaire about FIRE was applied to all participants. Skin prick tests were done on suspected patients to identify the triggering foods. FIRE is defined as suitable clinical symptoms with suspected food allergen exposure. Results A total of 78 patients (74.4% male, median age: 13.5 years) were included. Unpleasant and recurrent symptoms distinct from dysphagia with specific foods were reported in 16.7% of the patients, all of whom had concomitant allergic rhinitis (AR). The symptoms described by almost all patients were oropharyngeal itching and tingling (PFAS: 15.3%) excluding only one patient reporting retrosternal narrowing and pressure after specific food consumption (FIRE: 1.2%). Conclusions Although definitive conclusions regarding the true prevalence of FIRE cannot be made, it does not seem to be common as PFAS. However, it deserves questioning particularly in the presence of concurrent AR and/or PFAS in children with EoE.
Have we been qualifying measurable residual disease correctly?
Authors: Yahui Feng, Saibing Qi, Xueou Liu, Li Zhang, Yu Hu, Qiujin Shen, Xiaowen Gong, Wei Zhang, Junxia Wang, Wen Yan, Tiantian Wang, Huijun Wang, Zhen Song, Xiaofan Zhu, Robert Peter Gale, Junren Chen
Journal: Leukemia (2023)
Biomanufacturing of 3D Tissue Constructs in Microgravity and their Applications in Human Pathophysiological Studies (Adv. Healthcare Mater. 23/2023)
Authors: Zhanping Ren, Anicca D. Harriot, Devin B. Mair, Michael K. Chung, Peter H. U. Lee, Deok‐Ho Kim
Journal: Advanced Healthcare Materials (2023)

Microgravity Based Biomanufacturing In article 2300157, Peter H. U. Lee, Deok-Ho Kim, and co-workers discuss simulated and real microgravity platforms used to improve biomanufacturing of 3D tissue constructs and their use in studying pathophysiology of long duration space missions. Various microphysiological systems are presented, including organoid and organ-on-a-chip, which are fabricated and flown in microgravity to model specific human diseases and aging effects.
Early-Stage Breast Cancer Detection in Breast Milk
Authors: Cristina Saura, Carolina Ortiz, Judit Matito, Enrique J. Arenas, Anna Suñol, Ágatha Martín, Octavi Córdoba, Alex Martínez-Sabadell, Itziar García-Ruiz, Ignacio Miranda, Clara Morales-Comas, Estela Carrasco, Cristina Viaplana, Vicente Peg, Paolo Nuciforo, Neus Bayó-Puxan, Alberto Gonzalez-Medina, Josep M. Miquel, Marina Gómez-Rey, Guillermo Villacampa, Silvia Arévalo, Martín Espinosa-Bravo, Judith Balmaña, Rodrigo Dienstmann, Joaquin Arribas, Josep Tabernero, Ana Vivancos, Miriam Sansó
Journal: Cancer Discovery (2023)

Breast cancer occurring during pregnancy (PrBC) and postpartum (PPBC) is usually diagnosed at more advanced stages compared with other breast cancer, worsening its prognosis. PPBC is particularly aggressive, with increased metastatic risk and mortality. Thus, effective screening methods to detect early PrBC and PPBC are needed. We report for the first time that cell-free tumor DNA (ctDNA) is present in breast milk (BM) collected from patients with breast cancer. Analysis of ctDNA from BM detects tumor variants in 87% of the cases by droplet digital PCR, while variants remain undetected in 92% of matched plasma samples. Retrospective next-generation sequencing analysis in BM ctDNA recapitulates tumor variants, with an overall clinical sensitivity of 71.4% and specificity of 100%. In two cases, ctDNA was detectable in BM collected 18 and 6 months prior to standard diagnosis. Our results open up the potential use of BM as a new source for liquid biopsy for PPBC detection. For the first time, we show that BM obtained from patients with breast cancer carries ctDNA, surpassing plasma-based liquid biopsy for detection and molecular profiling of early-stage breast cancer, even prior to diagnosis by image. See related commentary by Cunningham and Turner, p. 2125. This article is featured in Selected Articles from This Issue, p. 2109.
Cyclic Stretching Triggers Cell Orientation and Extracellular Matrix Remodeling in a Periodontal Ligament 3D In Vitro Model
Authors: Kuo‐Hui Chiu, Mert Karpat, Johannes Hahn, Kao‐Yuan Chang, Michael Weber, Michael Wolf, Sanja Aveic, Horst Fischer
Journal: Advanced Healthcare Materials (2023)

Abstract During orthodontic tooth movement (OTM), the periodontal ligament (PDL) plays a crucial role in regulating the tissue remodeling process. To decipher the cellular and molecular mechanisms underlying this process in vitro, suitable 3D models are needed that more closely approximate the situation in vivo. Here, a customized bioreactor is developed that allows dynamic loading of PDL‐derived fibroblasts (PDLF). A collagen‐based hydrogel mixture is optimized to maintain structural integrity and constant cell growth during stretching. Numerical simulations show a uniform stress distribution in the hydrogel construct under stretching. Compared to static conditions, controlled cyclic stretching results in directional alignment of collagen fibers and enhances proliferation and spreading ability of the embedded PDLF cells. Effective force transmission to the embedded cells is demonstrated by a more than threefold increase in Periostin protein expression. The cyclic stretch conditions also promote extensive remodeling of the extracellular matrix, as confirmed by increased glycosaminoglycan production. These results highlight the importance of dynamic loading over an extended period of time to determine the behavior of PDLF and to identify in vitro mechanobiological cues triggered during OTM‐like stimulus. The introduced dynamic bioreactor is therefore a useful in vitro tool to study these mechanisms.
Comparison of 18F-FDG PET Findings of Pegfilgrastim-Induced Aortitis With Other Types of Large-Vessel Vasculitis
Authors: Atsushi Takamatsu, Kotaro Yoshida, Satoru Watanabe, Takahiro Komori, Dai Inoue, Junichi Taki, Toshifumi Gabata
Journal: Clinical Nuclear Medicine (2023)

To elucidate the PET/CT findings of pegfilgrastim-induced aortitis (PFIA) and compare them with those of other large-vessel vasculitis.We enrolled 45 patients diagnosed with the following: PFIA, n = 8; Takayasu arteritis (TA), n = 12; giant cell arteritis (GCA), n = 6; and immunoglobulin G4-related aortitis (IgG4-A), n = 19. Records of PET/CT performed before treatment initiation were collected. The aorta and its branches were divided into 16 anatomic regions. Presence of abnormal 18 F-FDG uptake in each region was determined and measured.The 18 F-FDG-positive areas of PFIA were distributed in the regions of the ascending aorta to the suprarenal abdominal aorta, cervical branches of the aorta, and external iliac arteries, similar to those of TA. However, TA had a higher proportion of 18 F-FDG-positive areas than PFIA in almost all anatomic regions. These areas of GCA were widespread throughout the entire aorta and the upper and lower limbs, whereas those of IgG4-A were observed from the abdominal aorta to iliac arteries. SUV max , SUV peak , metabolic volume, and total lesion glycolysis were higher in GCA than in PFIA, TA, and IgG4-A.Pegfilgrastim-induced aortitis distribution on PET/CT was frequently observed in the aorta, cervical branches, and extra iliac arteries. The low proportion of 18 F-FDG-positive areas in PFIA was different from that of TA, GCA, and IgG4-A. These findings may help identify and differentiate various aortitis types in clinical practice.
Brain 18F-FET in a Case of Acute Myeloid Leukemia
Authors: Angelo Castello, Giacomo Crosta, Sara Pacella, Luigia Florimonte, Massimo Castellani
Journal: Clinical Nuclear Medicine (2023)

A 58-year-old woman, with a history of acute myeloid leukemia in complete response, was referred to the emergency department of our hospital for loss of consciousness. A brain MRI showed an intracranial mass suggestive for either primary brain tumor or brain metastasis. 18 F-FET PET/CT revealed increased uptake of the lesion. Metastasis from acute myeloid leukemia was diagnosed after brain biopsy. Whole-body 18 F-FDG PET/CT did not demonstrate other abnormal foci of 18 F-FDG accumulation, whereas brain lesion had an uptake slightly below the adjacent brain.